Inhibitors of farnesyl-protein transferase

- Merck & Co., Inc.

The present invention is directed to piperazine-2,3-dione compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

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Claims

1. A compound which inhibits farnesyl-protein transferase of the formula A: ##STR27## wherein: R.sup.1a and R.sup.1b are independently selected from:

a) hydrogen,
b) aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN(R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
vc) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.3 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N-- C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.10 C(O)--NR.sup.10 --;
R.sup.2 and R.sup.3 are independently selected from: H; unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, ##STR28## wherein the substituted group is substituted with one or more of: ##STR29## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4, R.sup.6 and R.sup.7 are independently selected from: H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) aryl,
c) halogen,
d) HO, ##STR30## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2; or
R.sup.5 is selected from: C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) aryl,
c) halogen,
d) HO, ##STR31## f) --SO.sub.2 R.sup.11 or g) N(R.sup.10).sub.2;
R.sup.8 is independently selected from:
a) hydrogen,
b) aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NH--;
R.sup.9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.10 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m;
V is selected from:
a) hydrogen,
b) aryl,
c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
d) C.sub.2 -C.sub.20 alkenyl,
W is imidazolyl;
X is bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m --;
Z is selected from:
1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C.sub.1-4 alkyl, unsubstituted or substituted with:
C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
b) aryl,
c) halogen,
d) OR.sup.4,
e) NR.sup.4 R.sup.6,
f) CN,
g) NO.sub.2,
h) CF.sub.3;
i) --S(O).sub.m R.sup.5,
j) --C(O)NR.sup.4 R.sup.6, or
k) C.sub.3 -C.sub.6 cycloalkyl; and
2) unsubstituted C.sub.1-C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
a) C.sub.1-4 alkoxy,
b) NR.sup.4 R.sup.6,
c) C.sub.3-6 cycloalkyl,
d) --NR.sup.4 C(O)R.sup.6,
e) HO,
f) --S(O).sub.m R.sup.5,
g) halogen, or
h) perfluoroalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 1; and
u is 4 or 5;

2. The compound according to claim 1 of the formula A: ##STR32## wherein: R.sup.1a is independently selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;

R.sup.1b is independently selected from:
a) hydrogen,
b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, cycloalkyl, alkenyl, R.sup.10 O-- and -N(R.sup.10).sub.2;
R.sup.3 is selected from H and CH.sub.3;
R.sup.2 is selected from H; ##STR33## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) OR.sup.4,
3) SR.sup.5, SO.sub.2 R.sup.5, or ##STR34## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.5 is selected from:
C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.8 is independently selected from:
a) hydrogen,
b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10)2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.9 is selected from:
a) hydrogen,
b) C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sup.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.11 S(O).sup.m --, R.sup.10 C(O)NR.sup.10 --, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, O, --N(R.sup.10)-- and S(O).sub.m;
V is selected from:
a) hydrogen,
b) aryl,
c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
d) C.sub.2 -C.sub.20 alkenyl, and
W is imidazolyl;
X is --CH.sub.2 -- or --C(.dbd.O)--;
Z is selected from:
1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C.sub.1-4 alkyl, unsubstituted or substituted with:
C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
b) aryl,
c) halogen,
d) OR.sup.4,
e) NR.sup.4 R.sup.6,
f) CN,
g) NO.sub.2,
h) CF.sub.3;
i) --S(O).sub.m R.sup.5,
j) --C(O)NR.sup.4 R.sup.6, or
k) C.sub.3 -C.sub.6 cycloalkyl; and
2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1-C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
a) C.sub.1-4 alkoxy,
b) NR.sup.4 R.sup.6,
c) C.sub.3-6 cycloalkyl,
d) --NR.sup.4 C(O)R.sup.6,
e) HO,
f) --S(O).sub.m R.sup.5,
g) halogen, or
h) perfluoroalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
t is 1; and
u is 4or 5;

3. The compound according to claim 1 of the formula B: ##STR35## wherein: R.sup.1a is selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;

R.sup.1b is independently selected from:
a) hydrogen,
b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
c) C.sup.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
R.sup.3 is selected from H and CH.sub.3;
R.sup.2 is selected from H; ##STR36## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) OR.sup.4,
3) SR.sup.5, SO.sub.2 R.sup.5, or ##STR37## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.5 is selected from:
C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.8 is independently selected from:
a) hydrogen,
b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10), R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.9 a is hydrogen or methyl;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, O, --N(R.sup.10)--, or S(O).sub.m;
V is selected from:
a) hydrogen,
b) aryl,
c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
d) C.sub.2 -C.sub.20 alkenyl, and
X is --CH.sub.2 -- or --C(.dbd.O)--;
Z is selected from:
1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C.sub.1-4 alkyl, unsubstituted or substituted with:
C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
b) aryl,
c) halogen,
d) OR.sup.4,
e) NR.sup.4 R.sup.6,
f) CN,
g) NO.sub.2,
h) CF.sub.3;
i) --S(O).sub.m R.sup.5,
j) --C(O)NR.sup.4 R.sup.6, or
k) C.sub.3 -C.sub.6 cycloalkyl; and
2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
a) C.sub.1-4 alkoxy,
b) NR.sup.4 R.sup.6,
c) C.sub.3-6 cycloalkyl,
d) --NR.sup.4 C(O)R.sup.6,
e) HO,
f) --S(O).sub.m R.sup.5,
g) halogen, or
h) perfluoroalkyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and
r is 0 to 5, provided that r is 0 when V is hydrogen;

4. The compound according to claim 3 of the formula C: ##STR38## wherein: R.sup.1b is independently selected from:

a) hydrogen,
b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
R.sup.3 is selected from H and CH.sub.3;
R.sup.2 is selected from H; ##STR39## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) OR.sup.4,
3) SR.sup.5, SO.sub.2 R.sup.5, or
4) ##STR40## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.5 is selected from:
C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.8 is independently selected from:
a) hydrogen,
b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.1 OC(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.10 is independently selected from hydrogen, C.sup.1 -C.sub.6 alkyl, benzyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
X is --CH.sub.2 -- or --C(.dbd.O)--;
Z is selected from:
1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
a) C.sub.1-4 alkyl, unsubstituted or substituted with:
C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
b) aryl,
c) halogen,
d) OR.sup.4,
e) NR.sup.4 R.sup.6,
f) CN,
g) NO.sub.2,
h) CF.sub.3;
i) --S(O).sub.m R.sup.5,
j) --C(O)NR.sup.4 R.sup.6, or
k) C.sub.3 -C.sub.6 cycloalkyl; and
2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
a) C.sub.1-4 alkoxy,
b) NR.sup.4 R.sup.6,
c) C.sub.3-6 cycloalkyl,
d) --NR.sup.4 C(O)R.sup.6,
e) HO,
f) --S(O).sub.m R.sup.5,
g) halogen, or
h) perfluoroalkyl;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4;

5. The compound according to claim 4 of the formula D: ##STR41## wherein: R.sup.1b is independently selected from:

a) hydrogen,
b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
R.sup.2 and R.sup.3 are independently selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;
R.sup.4 and R.sup.6 are independently selected from:
H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) halogen, or
c) aryl;
R.sup.5 is selected from:
C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
a) C.sub.1- 4 alkoxy,
b) halogen, or
c) aryl;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
X is --CH.sub.2 -- or --C(.dbd.O)--;
Z is mono- or bicyclic aryl, mono- or bicyclic arylmethyl or mono- or bicyclic arylsulfonyl, unsubstituted or substituted with one or two of the following:
1) C.sub.1-4 alkyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) NR.sup.4 R.sup.6,
c) C.sub.3-6 cycloalkyl,
d) aryl,
e) HO,
f) --S(O).sub.m R.sup.5, or
g) --C(O)NR.sup.4 R.sup.6,
2) aryl,
3) halogen,
4) OR.sup.4,
5) NR.sup.4 R.sup.6,
6) CN,
7) NO.sub.2,
8) CF.sub.3;
9) --S(O).sub.m R.sup.5,
10) --C(O)NR.sup.4 R.sup.6, or
11) C.sub.3 -C.sub.6 cycloalkyl;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4;

9. The compound according to claim 5 which is:

1-(4-imidazolyl)-4-(2,3-dimethylphenyl)piperazine-2,3-dione ##STR44## or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.

11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2.

12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3.

13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6.

14. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

Referenced Cited
U.S. Patent Documents
5576313 November 19, 1996 Fisher et al.
Foreign Patent Documents
0 670 314 A1 September 1995 EPX
WO 96/30343 October 1996 WOX
WO 96/37204 November 1996 WOX
Other references
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Patent History
Patent number: 5859012
Type: Grant
Filed: Mar 25, 1997
Date of Patent: Jan 12, 1999
Assignee: Merck & Co., Inc. (Rahway, NJ)
Inventors: Christopher J. Dinsmore (Schwenksville, PA), Theresa M. Williams (Harleysville, PA)
Primary Examiner: Emily Bernhardt
Attorneys: David A. Muthard, Mark R. Daniel
Application Number: 8/823,923